Neoplasia is a process that occurs in cancer, by which the normal controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in progressive growth. This impairment of control mechanisms allows a tumor to enlarge and occupy spaces in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites it will likely result in death of the individual.
The desired goal of cancer therapy is to kill cancer cells preferentially, without having a deleterious effect on normal cells. Several methods have been used in an attempt to reach this goal, including surgery, radiation therapy, and chemotherapy.
Local treatments, such as radiation therapy and surgery, offer a way of reducing the tumor mass in regions of the body that are accessible through surgical techniques or high doses of radiation therapy. However, more effective local therapies with fewer side effects are needed. Moreover, these treatments are not applicable to the destruction of widely disseminated or circulating tumor cells eventually found in most cancer patients. To combat the spread of tumor cells, systemic therapies are used.
The primary weapon against cancer is chemotherapy. However, chemotherapeutic agents are limited in their effectiveness for treating many cancer types, including many common solid tumors. This failure is in part due to the intrinsic or acquired drug resistance of many tumor cells. Another drawback to the use of chemotherapeutic agents is their severe side effects. These include bone marrow suppression, nausea, vomiting, hair loss, and ulcerations in the mouth.
Proposed alternative therapies include the administration of oncolytic viruses, and the use of viral vectors to deliver a transgene whose expression product activates a chemotherapeutic agent. The genetic engineering of viruses for use as oncolytic agents has initially focused on the use of replication-incompetent viruses. This strategy was hoped to prevent damage to non-tumor cells by the viruses. A major limitation of this approach is that these replication-incompetent viruses require a helper virus to be able to integrate and/or replicate in a host cell. These viruses are limited in their effectiveness, because each replication-defective retrovirus particle can enter only a single cell and cannot productively infect others thereafter. Therefore, they cannot spread far from the producer cell, and are unable to completely penetrate many tumors in vivo. More recently, genetic engineering of oncolytic viruses has focused on the generation of “replication-conditional” viruses in an attempt to avoid systemic infection, while allowing the virus to spread to other tumor cells. Replication-conditional viruses are designed to preferentially replicate in actively dividing cells, such as tumor cells. Thus, these viruses should target tumor cells for oncolysis, and replicate in these cells so that the virus can spread to other tumor cells.
However, while the virus-based approach has provided evidence of significant therapeutic effects in animal models of tumors, the method is limited by the efficiency of viral infection; the requirement of a helper virus or producer cell line for some viral vectors; tumor cell heterogeneity for the cellular factor(s) complementing viral mutant growth for other viral vectors; and antiviral immune responses.
A variety of immune cell-based cancer therapies have also been proposed, many of which rely on the identification of tumor-associated antigens that are often weak or expressed on only a subset of tumor cells. Cytokine induced killer (CIK) cells are a population of cells derived from human PBMC's following ex vivo expansion with γIFN, anti-CD3 antibody and IL-2. They bear phenotypic markers of NK and T cells, express NKG2D and have been found to mediate killing of tumor cells through recognition of a class of stress-associated ligands expressed on the tumor cell surface (NKG2D ligands). CIK cells therefore do not rely on specific antigens and they have also been shown to target a variety of tumors and exert their cytotoxic effects following systemic delivery. Previous pre-clinical imaging studies found that at 72 hours (h) after intravenous delivery signals from CIK cells were found primarily at the tumor site. However, tumor cell killing required effector to target ratios of five to ten CIK cells per tumor cell in vitro, and a dependence on over expression of NKG2D ligands on the tumor targets.
Targeted biological therapies hold tremendous potential for the treatment of cancers, yet their effective use has been limited by constraints on delivery and effective tumor targeting. There exists a need for a local therapy that provides for effective killing of tumor cells. The present invention addresses this need.